Project Summary/Abstract This project is aimed at developing a new type of optical nano-probes for targeted molecular imaging of tumors. Specifically, these nano-probes are hybrid structures composed of an erythrocyte-derived membrane shell that encapsulates indocyanine green (ICG), the only FDA-approved near infrared (NIR) chromophore. We refer to these nano-probes as NIR erythrocyte-derived transducers (NETs). Our long-term goal is to commercialize the NETs as fluorescent probes for intraoperative imaging, or in conjunction with endoscopic procedures to aid visualization of tumor margins and small tumor nodules (< 0.5 mm diameter) that cannot otherwise be detected by current imaging techniques. New imaging methods that can identify tumor margins, and small tumor nodules when they are still at an early stage or localized, will have tremendous clinical impact by enabling image-guided identification for resection of all tumors to reduce or eliminate cancer recurrence and ultimately improve treatment success and patient survival. Such capabilities are not currently available, and if achieved, will impact the clinical management of patients with various types of solid cancers to reduce the burden of cancer and the deaths resulting from it. There are no prior reports of such constructs for optical imaging of tumors. Therefore, this proposal presents a highly innovative technology in tumor imaging, and the first step in investigating the potential of these materials for future clinical translation during intraoperative or endoscopic procedures to aid identification of tumor margins and small tumor nodules. Our specific aims (SAs) during this Phase I project are to: (1) optimize the formulation of NETs to maximal their fluorescence emission (SA1); (2) functionalize the NETs with Herceptin, an FDA-approved monoclonal antibody, for recognition of cancer cells by targeting the HER2 receptor (SA2), a key biomarker whose over-expression is associated with carcinogenesis of various solid tumors such as breast, ovarian, non-small cell lung cancer, and colorectal cancers; and (3) demonstrate the feasibility of using the functionalized NETs as nano-probes for targeted imaging of tumors in a mouse model (SA3). Upon completion of the proposed Phase I studies, we will have identified the optimum formulation of NETs with maximal fluorescence emission, and demonstrated feasibility for targeted imaging of tumors. Our activities during Phase II will include characterizing the biodistribution of NETs to determine the dynamics of the imaging sensitivity, and development of fabrication standardization procedures and full commercialization plans. Key commercial applications are: (1) intraoperative assessment of disseminated cancer; (2) minimally invasive or endoscopic assessment; and (3) small animal imaging applications. The business model for the commercialization of the proposed optical nano-probes hinges on established and validated business models associated with contrast agents or established molecular tags, which represent low risk models for the commercialization of NETs as products. This Phase I application is the first step towards these endeavors.